It is well known that the effect of a pharmaceutically-active ingredient administered to the body depends greatly on the administration route. Ideally of course one wants to create a concentration of the active ingredient localised at the affected site, but there is seldom a practical way of achieving this directly. For many drugs parenteral administration (e.g. intravenous, subcutaneous, intramuscular) is most effective but it has well known limitations and disadvantages. These include the risk of adverse effects from local high concentrations of drug substance in the body, the risk of infection at injection sites and in general a measure of discomfort or inconvenience tending to reduce patient compliance. Patient compliance is very important where a drug is to be routinely self-administered.
Other routes exploit drug transport across epithelial barriers, e.g buccal, nasal, vaginal, rectal and intestinal. Among these, enteral and particularly oral administration is by far the most convenient and favoured by patients. However enteral drug delivery is notoriously problematic because of the very indirect route by which the active ingredient enters the system. To show a therapeutic effect an orally-administered drug must survive the acidic environment of the stomach and then cross the epithelial barrier i.e. the gut lining in order to enter the circulation or interact with the immune system.
A number of published and practical proposals exist for coating and/or encapsulating pharmaceutically-active ingredients in excipients which allow the active substance to pass through the stomach and survive until they reach the target region of the GIT. One formulation type of particular current interest is the so called microparticles and nanoparticles, made of bioerodible or biodegradable polymeric excipients which can retain and protect the active substance as it travels along the GIT and then be absorbable through the gut wall, after which the particles should break down in the bloodstream and release the active ingredient to exert its therapeutic effect.
In practice however it has been found that bioavailability with these formulations is nevertheless much lower than with parenteral routes and also highly variable from one patient to another. This is generally regarded as being because of the difficulty in getting the active substance, in its bioerodible/biodegradable encapsulation where present, across the gut wall with its mucosal layer and highly selective epithelial cells.
Particular challenges in this respect arise in relation to the pharmaceutical use of biological or biotechnology products such as hormones and enzymes. These are generally macromolecular, e.g. proteins, peptides, genes, pieces of DNA, DNA vaccines, antisense oligonucleotides etc. Their large molecular size makes it difficult for them to cross the epithelium. Their stability in the GIT is poor because of the action of acids and enzymes. The bioavailability via the oral route is therefore a very low percentage, which is doubly problematic having in mind such drugs' scarcity and expense. Currently only parenteral administration is usable, with its attendant disadvantages. It would be highly desirable to improve the bioavailability of these macromolecular drugs and vaccines via other routes.
Various proposals have been published relating to means for giving drug-active particles a positive affinity to the gut wall so that whatever transepithelial mechanism operated would have a persistent presence of the active substance to work on, and/or some biochemical incentive to promote cellular uptake of the active.
Some work has been done on this and it has been pointed out and shown that various lectins—naturally-occurring protein substances with specific affinities for certain sugar residues—will bind specifically to model enterocyte-type cell lines. This is because the enterocyte surface displays oligosaccharide moieties. It has therefore been proposed to use lectins as carriers for oral drug delivery, particularly taking into account that non-toxic plant lectins are already in the human diet. Reference is made to the following publications. F. Gabor et al, Journal of Controllable Release 55 (1998), pp 131–142: N. Foster et al, Vaccine 16, No. 5 (1998), pp 536–541: C. M. Lehr et al, Pharm Res. 12 (1992) pp 547–553, and other articles on related themes.
Despite these interesting results, the use of lectins to promote “bioadhesion” of drug substances in the GIT remains problematic, because such large protein molecules are liable to degradation and loss of activity both in the gut under the action of enzymes and during processing to prepare formulations. This large size, together with potential immunogenicity and cytotoxicity effects, limits the use of lectins per se as targeting agents to deliver drugs and vaccines to and across the human GIT.
The present inventors have carried out very extensive investigations with a view to identifying, testing and preparing alternative substances showing an affinity for epithelial cells, and hence a “bioadhesive” capacity making them useful as moieties, ingredients or coatings in enterally-administered pharmaceutical formulations.